The mechanisms whereby initial glomerular injury serves as a determinant for the progression to end-stage renal disease (ESRD) are not completely understood. The long-term objectives of this proposal are to investigate the potential role(s) of the glomerular macrophage and filtered protein constituent fractions as determinants of chronic glomerular injury in aminonucleoside nephrosis; a triphasic model of experimental nephrotic syndrome consisting of acute nephrosis, spontaneous recovery, followed finally by recurrent proteinuria with glomerulosclerosis. In regards to the glomerular macrophage, these cells have been found to vary in relation to the initial proteinuria in aminonucleoside nephrosis; however, the pathologic significance of the numerical modulation, of these cells is unknown. Because the glomerular macrophage has been shown to produce cytokines, mitogens, toxic oxygen metabolites, and other vasoactive substances, it is intended to assess the effect of pharmacologic (i.e., mechlorethamine and anti-rat macrophage antiserum) reduction in glomerular macrophage number on the acute and chronic glomerular injury phases of aminonucleoside nephrosis. Additionally, attempts will be made to alter monocyte/macrophage functions, in vivo, using dietary maneuvers (e.g., hypercholesterolemic diet) and pharmacologic means, including: thromboxane synthetase A2 and 5- lipoxygenase inhibitors; thromboxane A2 and LTC4/LTD4 receptor antagonists. It is anticipated that modulation of monocyte/macrophage function during a reversible acute nephrotic syndrome will alter the glomerular hemodynamics, renal function, and glomerular morphology in subsequent phases of chronic aminonucleoside nephrosis. A second aspect of this proposal is to assess the cytotoxic effect of various filtered protein constituent fractions on normal rat proximal tubule suspensions. This is based on a hypothesis that excess filtered protein during acute nephrosis causes tubular epithelial damage, and this process may be integral to the tubulointerstitial morphologic abnormalities which develop in glomerular disorders. Tubular epithelial functions to be evaluated include: ion transport, mitochondrial oxidative metabolism, and membrane permeability. These combined studies will help to clarify our understanding of the role of macrophage and filtered protein constituents as determinants of progressive glomerular injury.